Heterocyclic ester and amide hair growth compositions and uses

ABSTRACT

This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using heterocyclic esters or amides.

BACKGROUND OF THE INVENTION

1. Field of Invention

This invention relates to pharmaceutical compositions and methods fortreating alopecia and promoting hair growth using low molecular weight,small molecule heterocyclic esters or amides.

2. Description of Related Art

Hair loss occurs in a variety of situations. These situations includemale pattern alopecia, alopecia senilis, alopecia areata, diseasesaccompanied by basic skin lesions or tumors, and systematic disorderssuch as nutritional disorders and internal secretion disorders. Themechanisms causing hair loss are very complicated, but in some instancescan be attributed to aging, genetic disposition, the activation of malehormones, the loss of blood supply to hair follicles, and scalpabnormalities.

The immunosuppressant drugs FKSO6, rapamycin and cyclosporin are wellknown as potent T-cell specific immunosuppressants, and are effectiveagainst graft rejection after organ transplantation. It has beenreported that topical, but not oral, application of FK506 (Yamamoto etal., J. Invest. Dermatol., 1994, 102, 160-164; Jiang et al., J. Invest.Dermatol. 1995, 104, 523-525) and cyclosporin (Iwabuchi et al., J.Dermatol. Sci. 1995, 9, 64-69) stimulates hair growth in adose-dependent manner. One form of hair loss, alopecia areata, is knownto be associated with autoimmune activities; hence, topicallyadministered immunomodulatory compounds are expected to demonstrateefficacy for treating that type of hair loss. The hair growthstimulating effects of FK506 have been the subject of an internationalpatent filing covering FK506 and structures related thereto for hairgrowth stimulation (Honbo et al., EP 0 423 714 A2). Honbo et al.discloses the use of relatively large tricyclic compounds, known fortheir immunosuppressive effects, as hair revitalizing agents.

The hair growth and revitalization effects of FK506 and related aaentsare disclosed in many U.S. Patents (Goulet et al., U.S. Pat. No.5,258,389; Luly et al., U.S. Pat. No. 5,457,111; Goulet et al., U.S.Pat. No. 5,532,248; Goulet et al., U.S. Pat. No. 5,189,042; and Ok etal., U.S. Pat. No. 5,208,241; Rupprecht et al., U.S. Pat. No. 5,284,840;Organ et al., U.S. Pat. No. 5,284,877). These patents claim FK506related compounds. Although they do not claim methods of hairrevitalization, they disclose the known use of FK506 for effecting hairgrowth. Similar to FK506 (and the claimed variations in the Honbo et al.patent), the compounds claimed in these patents are relatively large.Further, the cited patents relate to immunomodulatory compounds for usein autoimmune related diseases, for which FK506's efficacy is wellknown.

Other U.S. patents disclose the use of cyclosporin and related compoundsfor hair revitalization (Hauer et al., U.S. Pat. No. 5,342,625; Eberle,U.S. Pat. No. 5,284,826; Hewitt et al., U.S. Pat. No. 4,996,193). Thesepatents also relate to compounds useful for treating autoimmune diseasesand cite the known use of cyclosporin and related immunosuppressivecompounds for hair growth.

However, immunosuppressive compounds by definition suppress the immunesystem and also exhibit other toxic side effects. Accordingly, there isa need for non-immunosuppressant, small moleculas compounds which areuseful as hair revitalizing compounds.

Hamilton and Steiner disclose in U.S. Pat. No. 5,614,547 novelpyrrolidine carboxylate compounds which bind to the immunophilin FKBP12and stimulate nerve growth, but which lack immunosuppressive effects.Unexpectedly, it has been discovered that these non-immunosuppressantcompounds promote hair growth with an efficacy similar to FK506. Yettheir novel small molecule structure and non-immunosuppressiveproperties differentiate them from FK506 and related immunosuppressivecompounds found in the prior art.

SUMMARY OF THE INVENTION

The present invention relates to a method for treating alopecia orpromoting hair growth in an animal, which comprises administering tosaid animal an effective amount of a heterocyclic ester or amide.

The present invention further relates to a pharmaceutical compositionwhich comprises:

(i) an effective amount of a heterocyclic ester or amide for treatingalopecia or promoting hair growth in an animal; and

(ii) a pharmaceutically acceptable carrier.

The heterocyclic esters and amides used in the inventive methods andpharmaceutical compositions have an affinity for FKBP-type immunophilinsand do not exert any significant immunosuppressive activity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a photograph of C57 Black 6 mice before being shaved for thehair regeneration experiment.

FIG. 2 is a photograph of mice treated with a vehicle after six weeks.FIG. 2 shows that less than 3% of the shaved area is covered with newhair growth when the vehicle (control) is administered.

FIG. 3 is a photograph of mice treated with 10 μM of GPI 1046, a relatednon-immunosuppressive neuroimmunophilin FKBP ligand, after six weeks.FIG. 3 shows the remarkable effects of neuroimmunophilin FKBP ligands,wherein 90% of the shaved area is covered with new hair growth.

FIG. 4 is a photograph of mice treated with 30 AM of GPI 1046, a relatednon-immunosuppressive neuroimmunophilin FKBP ligand, after six weeks.FIG. 4 shows the remarkable ability of neuroimmunophilin FKBP ligands toachieve, essentially, complete hair regrowth in the shaved area.

FIG. 5 is a bar graph depicting the relative hair growth indices for C57Black 6 mice treated with a vehicle, FK506, and variousnon-immunosuppressive neuroimmunophilin FKBP ligands, including GPI1572, 14 days after treatment with each identified compound. FIG. 5demonstrates the remarkable early hair growth promoted by a wide varietyof non-immunosuppressive neuroimmunophilin FKBP ligands.

DETAILED DESCRIPTION OF THE INVENTION Definitions

“Alopecia” refers to deficient hair growth and partial or complete lossof hair, including without limitation androgenic alopecia (male patternbaldness), toxic alopecia, alopecia senilis, alopecia areata, alopeciapelada and trichotillomania. Alopecia results when the pilar cycle isdisturbed. The most frequent phenomenon is a shortening of the hairgrowth or anagen phase due to cessation of cell proliferation. Thisresults in an early onset of the catagen phase, and consequently a largenumber of hairs in the telogen phase during which the follicles aredetached from the dermal papillae, and the hairs fall out. Alopecia hasa number of etiologies, including genetic factors, aging, local andsystemic diseases, febrile conditions, mental stresses, hormonalproblems, and secondary effects of drugs.

“GPI 1605” refers to a compound of formula

“GPI 1046” refers to 3-(3-pyridyl)-1-propyl(2s)-1-(3,3-dimethyl-1,2-dioxopenty)-2-pyrrolidinecarboxylate, acompound of formula

“GPI 1312” refers to a compound of formula

“GPI 1572” refers to a compound of formula

“GPI 1389” refers to a compound of formula

“GPI 1511” refers to a compound of formula

“GPI 1234” refers to a compound of formula

“Isomers” refer to different compounds that have the same molecularformula. “Stereoisomers” are isomers that differ only in the way theatoms are arranged in space. “Enantiomers” are a pair of stereoisomersthat are non-superimposable mirror images of each other.“Diastereoisomers” are stereoisomers which are not mirror images of eachother. “Racemic mixture” means a mixture containing equal parts ofindividual enantiomers. “Non-racemic mixture” is a mixture containingunequal parts of individual enantiomers or stereoisomers.

“Pharmaceutically acceptable salt, ester, or solvate” refers to a salt,ester, or solvate of a subject compound which possesses the desiredpharmacological activity and which is neither biologically nor otherwiseundesirable. A salt, ester, or solvate can be formed with inorganicacids such as acetate, adipate, alginate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, naphthylate, 2-naphthalenesulfonate, nicotinate,oxalate, sulfate, thiocyanate, tosylate and undecanoate. Examples ofbase salts, esters, or solvates include ammonium salts; alkali metalsalts, such as sodium and potassium salts; alkaline earth metal salts,such as calcium and magnesium salts; salts with organic bases, such asdicyclohexylamine salts; N-methyl-D-glucamine; and salts with aminoacids, such as arginine, lysine, and so forth. Also, the basicnitrogen-containing groups can be quarternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chlorides,bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl,dibutyl, and diamyl sulfates; long chain halides, such as decyl, lauryl,myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halidessuch as benzyl and pheneththyl bromidesdes; and others. Water oroil-soluble or dispersible products are thereby obtained.

“Pilar cycle” refers to the life cycle of hair follicles, and includesthree phases:

(1) the anagen phase, the period of active hair growth which, insofar asscalp hair is concerned, lasts about three to five years;

(2) the catagen phase, the period when growth stops and the follicleatrophies which, insofar as scalp hair is concerned, lasts about one totwo weeks; and

(3) the telogen phase, the rest period when hair progressively separatesand finally falls out which, insofar as scalp hair is concerned, lastsabout three to four months. Normally 80 to 90 percent of the folliclesare in the anagen phase, less than 1 percent being in the catagen phase,and the rest being in the telogen phase. In the telogen phase, hair isuniform in diameter with a slightly bulbous, non-pigmented root. Bycontrast, in the anagen phase, hair has a large colored bulb at itsroot.

“Promoting hair growth” refers to maintainina, inducing, stimulating,accelerating, or revitalizing the germination of hair.

“Treating alopecia” refers to:

(i) preventing alopecia in an animal which may be predisposed toalopecia; and/or

(ii) inhibiting, retarding or reducing alopecia; and/or

(iii) promoting hair growth; and/or

(iv) prolonging the anagen phase of the hair cycle; and/or

(v) converting vellus hair to growth as terminal hair. Terminal hair iscoarse, pigmented, long hair in which the bulb of the hair follicle isseated deep in the dermis. Vellus hair, on the other hand, is fine,thin, non-pigmented short hair in which the hair bulb is locatedsuperficially in the dermis. As alopecia progresses, the hairs changefrom the terminal to the vellus type.

METHODS OF THE PRESENT INVENTION

The present invention relates to a method for treating alopecia orpromoting hair growth in an animal, which comprises administering tosaid animal an effective amount of a heterocyclic ester or amide.

The inventive method is particularly useful for treating male patternalopecia, alopecia senilis, alopecia areata, alopecia resulting fromskin lesions or tumors, alopecia resulting from cancer therapy such aschemotherapy and radiation, and alopecia resulting from systematicdisorders such as nutritional disorders and internal secretiondisorders.

PHARMACEUTICAL COMPOSITIONS OF THE PRESENT INVENTION

The present invention also relates to a pharmaceutical compositioncomprising:

(i) an effective amount of a heterocyclic ester or amide for treatingalopecia or promoting hair growth in an animal; and

(ii) a pharmaceutically acceptable carrier.

HETEROCYCLIC ESTERS AND AMIDES

The heterocyclic esters and amides used in the methods andpharmaceutical compositions of the present invention are low molecularweight, small molecule compounds having an affinity for an FKBP-typeimmunophilin, such as FKBP12. When a heterocyclic ester or amide bindsto an FKBP-type immunophilin, it has been found to inhibit theprolyl-peptidyl cis-trans isomerase, or rotamase, activity of thebinding protein. Unexpectedly, the compounds have also been found tostimulate hair growth. The compounds are devoid of any significantimmunosuppressive activity.

FORMULA I

The heterocyclic ester or amide may be a compound of formula I

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein:

A and B, together with the nitrogen and carbon atoms to which they arerespectively attached, form a 5-7 membered saturated or unsaturatedheterocyclic ring containing, in addition to the nitrogen atom, one ormore additional O, S, SO, SO₂, N, NH or NR₁ heteroatom(s);

X is O or S;

Z is O, NH or NR₁;

W and Y are independently O, S, CH₂ or H₂;

R₁ is C₁-C₆ straight or branched chain alkyl or C₂-C₆ straight orbranched chain alkenyl, which is substituted with one or moresubstituent(s) independently selected from the group consisting of(Ar₁)_(n), C₁-C₆ straight or branched chain alkyl or C₂-C₆ straight orbranched chain alkenyl substituted with (Ar₁)_(n), C₃-C₈ cycloalkyl,C₁-C₆ straight or branched chain alkyl or C₂-C₆ straight or branchedchain alkenyl substituted with C₃-C₈ cycloalkyl, and Ar₂;

n is 1 or 2;

R₂ is either C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain or alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar₁,wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is eitherunsubstituted or substituted with one or more substituent(s)independently selected from the group consisting of C₁-C₄ straight orbranched chain alkyl, C₂-C₄ straight or branched chain alkenyl, andhydroxyl; and

Ar₁ and Ar₂ are independently an alicyclic or aromatic, mono-, bi- ortricyclic, carbo- or heterocyclic ring, wherein the ring is eitherunsubstituted or substituted with one or more substituent(s)independently selected from the group consisting of halo, hydroxyl,nitro, trifluoromethyl, C₁-C₆ straight or branched chain alkyl, C₂-C₆straight or branched chain alkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy,phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-6members; and wherein the heterocyclic ring contains 1-6 heteroatom(s)independently selected from the group consisting of O, N, and S.

Suitable carbo- and heterocyclic rings include without limitationnaphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, quinolinyl,isoauinolinyl, fluorenyl and phenyl.

FORMULA II

Addicionally, the heterocyclic ester or amide may be a compound offormula II

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein:

A, B and C are independently CH₂, O, S, SO, SO₂, NH or NR₁;

R₁ is C₁-C₆ straight or branched chain alkyl or C₂-C₅ straight orbranched chain alkenyl, which is substituted with one or moresubstituent(s) independently selected from the group consisting of(Ar₁)_(n) and C₁-C₆ straight or branched chain alkyl or C₂-C₆ straightor branched chain alkenyl substituted with (Ar₁)_(n);

n is 1 or 2;

R₂ is either C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar₁;and

Ar₁ is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- orheterocyclic ring, wherein the ring is either unsubstituted orsubstituted with one or more substituent(s) independently selected fromthe group consisting of halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆straight or branched chain alkyl, C₂-C₆ straight or branched chainalkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino;wherein the individual ring size is 5-6 members; and wherein theheterocyclic ring contains 1-6 heteroatom(s) independently selected fromthe group consisting of O, N, and S.

In a preferred embodiment of the compounds of formula II, theheterocyclic ester or amide is the compound GPI 1572, of the formula

In a particularly preferred embodiment of formula II compounds:

A is CH₂;

B is CH₂ or S;

C is CH₂ or NH;

R₁ is selected from the group consisting of 3-phenylpropyl and3-(3-pyridyl)propyl; and

R₂ is selected from the group consisting of 1,1-dimethylpropyl,cyclohexyl, and tert-butyl.

Specific examples of this embodiment are presented in TABLE I.

TABLE I No. A B C R₁ R₂ 1 CH₂ S CH₂ 3-phenylpropyl 1,1-dimethylpropyl 2CH₂ S CH₂ 3-(3-pyridyl)propyl 1,1-dimethylpropyl 3 CH₂ S CH₂3-phenylpropyl cyclohexyl 4 CH₂ S CH₂ 3-phenylpropyl tert-butyl 5 CH₂CH₂ NH 3-phenylpropyl 1,1-dimethylpropyl 6 CH₂ CH₂ NH 3-phenylpropylcyclohexyl 7 CH₂ CH₂ NH 3-phenylpropyl tert-butyl

FORMULA III

The heterocyclic ester or amide may also be a compound of formula III

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein:

A, B, C and D are independently CH₂, O, S, SO, SO₂, NH or NR₁;

R₁ is C₁-C₆ straight or branched chain alkyl or C₂-C₆ straight orbranched chain alkenyl, which is substituted with one or moresubstituent(s) independently selected from the group consisting of(Ar₁)_(n) and C₁-C₆ straight or branched chain alkyl or C₂-C₆ straightor branched chain alkenyl substituted with (Ar₁)_(n);

n is 1 or 2;

R₂ is either C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl, C₃-C₉ cycloalkyl, C₁-C₇ cycloalkenyl, or Ar₁;and

Ar₁ is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- orheterocyclic ring, wherein the ring is either unsubstituted orsubstituted with one or more substituent(s) independently selected fromthe group consisting of halo, hydroxyl, nitro, trifluoromethyl, C₁-C₆straight or branched chain alkyl, C₂-C₆ straight or branched chainalkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino;wherein the individual ring size is 5-6 members; and wherein theheterocyclic ring contains 1-6 heteroatom(s) independently selected fromthe group consisting of O, N, and S.

In a particularly preferred embodiment of formula III compounds:

A is CH₂;

B is CH₂;

C is S, O or NH;

D is CH₂;

R₁ is selected from the group consisting of 3-phenylpropyl and(3,4,5-trimethoxy)phenylpropyl; and

R₂ s selected from the group consisting of 1,1-dimethylpropyl,cyclohexyl, tert-butyl, phenyl, and 3,4,5-trimethoxyphenyl.

Specific examples of this embodiment are presented in TABLE II.

TABLE II No. A B C D R₁ R₂  8 CH₂ CH₂ S CH₂ 3-phenyl- 1,1-dimethyl-propyl propyl  9 CH₂ CH₂ O CH₂ 3-phenyl- 1,1-dimethyl- propyl propyl 10CH₂ CH₂ S CH₂ 3-phenyl- cyclohexyl propyl 11 CH₂ CH₂ O CH₂ 3-phenyl-cyclohexyl propyl 12 CH₂ CH₂ S CH₂ 3-phenyl- phenyl propyl 13 CH₂ CH₂ OCH₂ 3-phenyl- phenyl propyl 14 CH₂ CH₂ NH CH₂ 3-phenyl- 1,1-dimethyl-propyl propyl 15 CH₂ CH₂ NH CH₂ 3-phenyl- phenyl propyl

FORMULA IV

The heterocyclic ester or amide may also be a compound of formula IV

or a prarmaceutically acceptable salt, ester, or solvate thereof,wherein:

V is C, N, or S;

A and B, taken together with V and the carbon atom to which they arerespectively attached, form a 5-7 membered saturated or unsaturatedheterocyclic ring containing, in addition to V, one or moreheteroatom(s) independently selected from the group consisting of O, S,SO, SO₂, N, NH, and NR;

R is either C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl, C₃-C₉ cycloakyl, C₅-C₇ cycloalkenyl, or Ar₃,wherein R is either unsubstituted or substituted with one or moresubstituent(s) independently selected from the group consisting of halo,haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C₁-C₆straight or branched chain alkyl, C₂-C₆ straight or branched chainalkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, thioalkyl,alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, andAr₄;

Ar₃ and Ar₄ are independently an alicyclic or aromatic, mono-, bi- ortricyclic, carbo- or heterocyclic ring; wherein the individual ring sizeis 5-8 members; wherein said heterocyclic ring contains 1-6heteroatom(s) independently selected from the group consisting of O, N,and S; and

R₁, R₂, W, X, Y, and Z are as defined in Formula I above.

All the compounds of Formulas I-IV possess asymmetric centers and thuscan be produced as mixtures of stereoisomers or as individual R- andS-stereoisomers. The individual stereoisomers may be obtained by usingan optically active starting material, by resolving a racemic ornon-racemic mixture of an intermediate at some appropriate stage of thesynthesis, or by resolving the compounds of Formulas I-IV. It isunderstood that the compounds of Formulas I-IV encompass individualstereoisomers as well as mixtures (racemic and non-racemic) ofstereoisomers. Preferably, S-stereoisomers are used in thepharmeceutical compositions and methods of the present invention.

Affinity for FKBP12

The compounds used in the inventive methods and pharmaceuticalcompositions have an affinity for the FK506 binding protein,particularly FKBP12. The inhibition of the prolyl peptidyl cis-transisomerase activity of FKBP may be measured as an indicator of thisaffinity.

K_(i) Test Procedure

Inhibition of the peptidyl-prolyl isomerase (rotamase) activity of thecompounds used in the inventive methods and pharmaceutical compositionscan be evaluated by known methods described in the literature (Hardinget al., Nature, 1939, 341: 758-760; Holt et al. J. Am. Chem. Soc.,115:9923-9938). These values are obtained as apparent K_(i)'s and arepresented for representative compounds in TABLE III.

The cis-trans isomerization of an alanine-proline bond in a modelsubstrate, N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide, is monitoredspectrophotometrically in a chymotrypsin-coupled assay, which releasesparanitroanilide from the trans form of the substrate. The inhibition ofthis reaction caused by the addition of different concentrations ofinhibitor is determined, and the data is analyzed as a change infirst-order rate constant as a function of inhibitor concentration toyield the apparent K_(i) values.

In a plastic cuvette are added 950 mL of ice cold assay buffer (25 mMHEPES, pH 7.8, 100 mM NaCl), 10 mL of FKBP (2.5 mM in 10 mM Tris-Cl pH7.5, 100 mM NaCl, 1 mM dithiothreitol), 25 mL of chymotrypsin (50 mg/mlin 1 mM HCl) and 10 mL of test compound at various concentrations indimethyl sulfoxide. The reaction is initiated by the addition of 5 mL ofsubstrate (succinyl-Ala-Phe-Pro-Phe-para-nitroanilide, 5 mg/mL in 2.35mM LiCl in trifluoroethanol).

The absorbance at 390 nm versus time is monitored for 90 seconds using aspectrophotometer and the rate constants are determined from theabsorbance versus time data files.

TABLE III In Vitro Test Results - Formulas I to IV Compound K_(i) (nM) 1215 2 638

Route of Administration

To effectively treat alopecia or promote hair growth, the compounds usedin the inventive methods and pharmaceutical compositions must readilyaffect the targeted areas. For these purposes, the compounds arepreferably administered topically to the skin.

For topical application to the skin, the compounds can be formulatedinto suitable ointments containing the compounds suspended or dissolvedin, for example, mixtures with one or more of the following: mineraloil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, the compounds can be formulated into suitable lotions orcreams containing the active compound suspended or dissolved in, forexample, a mixture of one or more of the following: mineral oil,sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearylalcohol, 2-octyldodecanal, benzyl alcohol and water.

Other routes of administraticn known in the pharmaceutical art are alsocontemplated by this invention.

Dosage

Dosage levels on the order of about 0.1 mg to about 10,000 mg of theactive ingredient compound are useful in the treatment of the aboveconditions, with preferred levels of about 0.1 mg to about 1,000 mg. Thespecific dose level for any particular patient will vary depending upona variety of factors, including the activity of the specific compoundemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration; the rate of excretion; drugcombination; the severity of the particular disease being treated; andthe form of administration. Typically, in vitro dosage-effect resultsprovide useful guidance on the proper doses for patient administration.Studies in animal models are also helpful. The considerations fordetermining the proper dose levels are well known in the art.

The compounds can be administered with other hair revitalizing agents.Specific dose levels for the other hair revitalizing agents will dependupon the factors previously stated and the effectiveness of the drugcombination.

EXAMPLES

The following examples are illustrative of the present invention and arenot intended to be limitations thereon. Unless otherwise indicated, allpercentages are based upon 100% by weight of the final composition.

Example 1 Synthesis of3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-thiazolidine)carboxylate(1)

1-(1,2-dioxo-2-methoxyethyl)2-(4-thiazolidine)-carboxylate

A solution of L-thioproline (1.51 g; 11.34 mmol)in 40 mL of drymethylene chloride was cooled to 0° C. and treated with 3.3 mL (2.41 g;23.81 mmol) of triethylamine. After stirring this mixture for 30minutes, a solution of methyl oxalyl chloride (1.81 g; 14.74 mmol) wasadded dropwise. The resulting mixture was stirred at 0° C. for 1.5hours, filtered through Celite to remove solids, dried and concentrated.The crude material was purified on a silic gel column, eluting with 10MeOH in methylene chloride, to obtain 2.0 g of the oxamate as anorange-yellow solid.

3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-methoxyethyl)2-(4-thiazolidine)carboxylate

1-(1,2-dioxo-2-methoxyethyl)2-(4-thiazolidine)carboxylate (500 mg; 2.25mmol), 3-phenyl-1-propanol (465 mg; 3.42 mmol), dicyclohexylcarbodiimide(750 mg; 3.65 mmol), 4-dimethylaminopyridine (95 mg; 0.75 mmol) andcamphorsulfonic acid (175 mg; 0.75 mmol) in 30 mL of methylene chloridewere stirred together overnight. The mixture was filtered through Celiteto remove solids and chromatographed (25% ethyl acetate/hexane) toobtain 690 mg of material. ¹H NMR (CDCl₃, 300 MHz): δ 1.92-2.01 (m, 2H);2.61-2.69 (m, 2H); 3.34 (m, 1H); 4.11-4.25 (m, 2H); 4.73 (m, 1H); 5.34(m, 1H); 7.12 (m, 3H); 7.23 (m, 2H).

3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-thiazolidine)carboxylate(1)

Asolution of3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-methoxyethyl)2-(4-thiazolidine)carboxylate(670 mg; 1.98 mmol) in tetrahydrofuran (10 mL) was cooled to −78° C. andtreated with 2.3 mL of a 1.0 M solution of 1,1-dimethylpropylmagnesiumchloride in ether. After stirring the mixture for 3 hours, it was pouredinto saturated ammonium chloride, extracted into ethyl acetate, and theorganic phase was washed with water, dried and concentrated. The crudematerial was purified on a silica gel column, eluting with 25% ethylacetate in hexane, to obtain 380 mg of the compound of Example 1 as ayellow oil. ¹H NMR (CDCl₃, 300 MHz): d 0.86 (t, 3H); 1.21 (s, 3H); 1.26(s, 3H); 1.62-1.91 (m, 3H); 2.01 (m, 2H); 2.71 (m, 2H); 3.26-3.33 (m,2H); 4.19 (m, 2H); 4.58 (m, 1H); 7.19 (m, 3H); 7.30 (m, 2H). Analysiscalculated for C₂₀H₂₇NO₄S: C, 63.63; H, 7.23 N, 3.71. Found: C, 64.29;H, 7.39; N, 3.46.

Example 2 Synthesis of3-(3-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-thiazolidine)carboxylate(2)

The compound of Example 2 was prepared according to the procedure ofExample 1, using 3-(3-pyridyl)-1-propanol in the final step, to yield3-(3-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-thiazolidine)carboxylate.¹H NMR (CDCl₃, 300 MHz): δ 0.89 (t, 3H, J=7.3); 1.25 (s, 3H); 1.28 (s,3H); 1.77 (q, 2H, J=7.3); 2.03 (tt, 2H, J=6.4, 7.5); 2.72 (t, 2H,J=7.5); 3.20 (dd, 1H, J=4.0, 11.8); 3.23 (dd, 1H, J=7.0, 11.8); 4.23 (t,2H, J=6.4); 4.55 (d, 2H, J=8.9); 5.08 (dd, 1H, J=4.0, 7.0); 7.24 (m,1H); 8.48 (m, 2H). Analysis calculated for C₁₉H₂₆N₂O₄S—0.5 H₂O: C,58.89; H, 7.02; N, 7.23. Found: C, 58.83; H, 7.05; N, 7.19.

Example 3 In Vivo Hair Generation Tests With C57 Black 6 Mice

Experiment A: C57 black 6 mice were used to demonstrate the hairrevitalizing properties of a low molecular weight, small molecule,non-immunosuppressive neuroimmunophilin FKBP ligand, GPI 1046, which isrelated to heterocyclic esters and amides. Referring now to FIGS. 1 and2 of the drawings, C57 black 6 mice, approximately 7 weeks old, had anarea of about 2 inches by 2 inches on their hindquarters shaved toremove all existing hair. Care was taken not to nick or cause abrasionto the underlaying dermal layers. The animals were in anagen growthphase, as indicated by the pinkish color of the skin. Referring now toFIGS. 2, 3 and 4, four animals per group were treated by topicaladministration with 20% propylene glycol vehicle (FIG. 2), 10 μM GPI1046 (FIG. 3) or 30 μM GPI 1046 (FIG. 4) dissolved in the vehicle. Theanimals were treated with vehicle or GPI 1046 every 48 hours (3applications total over the course of 5 days) and the hair growth wasallowed to proceed for 6 weeks. Hair growth was quantitated by thepercent of shaved area covered by new hair growth during this timeperiod.

FIG. 2 shows that animals treated with vehicle exhibited only a smallamount of hair growth in patches or tufts, with less than 3% of theshaved area covered with new growth. In contrast, FIG. 3 shows thatanimals treated with 10 μM GPI 1046 exhibited dramatic hair growth,covering greater than 90% of the shaved area in all animals. Further,FIG. 4 shows that mice treated with 30 μM GPI 1046 exhibited essentiallycomplete hair regrowth and their shaved areas were indistinguishablefrom unshaven C57 black 6 mice.

Experiment B: C57 Black 6 mice were used to demonstrate the hairrevitalizing properties of a variety of low molecular weight, smallmolecule, non-immunosuppressive neuroimmunophilin FKBP ligands,including GPI 1572. C57 Black 6 mice, 55 to 75 days old, had an area ofabout 2 inches by 2 inches on their hindquarters shaved to remove allexisting hair. Care was taken not to nick or cause abrasion to theunderlying dermal layers. The animals were in a anagen growth phase whenshaved. Five animals per group were treated by topical administrationwith vehicle, FKSO6, or one of the low molecular weight, small molecule,non-immunosuppressive neuroimmunophilin FKBP ligands (GPI 1605, 1046,1312, 1572, 1389, 1511, and 1234) at a concentration of one micromoleper milliliter to the shaved area. The animals were treated three timesper week, and hair growth was evaluated 14 days after initiation oftreatment. Hair growth was quantitated by the percent of shaved areacovered by new hair growth, as scored by a blinded observer, on a scaleof 0 (no growth) to five (complete hair regrowth in shaved area).

FIG. 5 shows that after 14 days, the animals treated with vehicleexhibited the beginning of growth in small tufts. In contrast, animalstreated with one of the low molecular weight, small molecule,non-immunosuppressive neuroimmunophilin FKBP ligands, including GPI1572, exhibited dramatic hair growth.

Example 4

A lotion comprising the following composition may be prepared.

(%) 95% Ethanol 80.0 a heterocyclic ester or 10.0 amide as defined aboveα-Tocopherol acetate  0.01 Ethylene oxide (40 mole)  0.5 adducts ofhardened castor oil purified water  9.0 perfume and dye q.s.

Into 95% ethanol are added a heterocyclic ester or amide, α-tocopherolacetate, ethylene oxide (40 mole) adducts of hardened castor oil,perfume and a dye. The resulting mixture is stirred and dissolved, andpurified water is added to the mixture to obtain a transparent liquidlotion.

5 ml of the lotion may be applied once or twice per day to a site havingmarked baldness or alopecia.

Example 5

A lotion comprising the following composition shown may be prepared.

(%) 95% Ethanol 80.0 a heterocyclic ester or   0.005 amide as definedabove Hinokitol  0.01 Ethylene oxide (40 mole)  0.5 adducts of hardenedcastor oil Purified water 19.0 Perfume and dye q.s.

Into 95% ethanol are added a heterocyclic ester or amide, hinokitol,ethylene oxide (40 mole) adducts of hardened castor oil, perfume, and adye. The resulting mixture is stirred, and purified water is added tothe mixture to obtain a transparent liquid lotion.

The lotion may be applied by spraying once to 4 times per day to a sitehaving marked baldness or alopecia.

Example 6

An emulsion may be prepared from A phase and B phase having thefollowing compositions.

(%) (A phase) Whale wax  0.5 Cetanol  2.0 Petrolatum  5.0 Squalane 10.0Polyoxyethylene (10 mole)  2.0 monostearate Sorbitan monooleate  1.0 aheterocyclic ester or  0.01 amide as defined above (B phase) Glycerine10.0 Purified water 69.0 Perfume, dye, and preservative q.s.

The A phase and the B phase are respectively heated and melted andmaintained at 80° C. Both phases are then mixed and cooled understirring to normal temperature to obtain an emulsion.

The emulsion may be applied by spraying once to four times per day to asite having marked baldness or alopecia.

Example 7

A cream may be prepared from A phase and B phase having the followingcompositions.

(%) (A phase) Fluid paraffin 5.0 Cetostearyl alcohol 5.5 Petrolatum 5.5Glycerine monostearate 33.0 Polyoxyethylene (20 mole) 3.0 2-octyldodecylether Propylparaben 0.3 (B Phase) a heterocyclic ester or 0.8 amide asdefined above Glycerine 7.0 Dipropylene glycol 20.0 Polyethylene glycol4000 5.0 Sodium Hexametaphosphate 0.005 Purified water 44.895

The A phase is heated and melted, and maintained at 70° C. The B phaseis added into the A phase and the mixture is stirred to obtain anemulsion. The emulsion is then cooled to obtain a cream.

The cream may be applied once to 4 times per day to a site having markedbaldness or alopecia.

Example 8

A liquid comprising the following composition may be prepared.

(%) Polyoxyethylene butyl ether 20.0 Ethanol 50.0 a heterocyclic esteror 0.001 amide as defined above Propylene glycol 5.0 Polyoxyethylenehardened castor 0.4 oil derivative (ethylene oxide 80 mole adducts)Perfume q.s. Purified water q.s.

Into ethanol are added polyoxypropylene butyl ether, propylene glycol,polyoxyethylene hardened castor oil, a heterocyclic ester or amide, andperfume. The resulting mixture is stirred, and purified water is addedto the mixture to obtain a liquid.

The liquid may be applied once to 4 times per day to a site havingmarked baldness or alopecia.

Example 9

A shampoo comprising the following composition may be prepared.

(%) Sodium laurylsulfate 5.0 Triethanolamine laurylsulfate 5.0 Betainelauryldimethylaminoacetate 6.0 Ethylene glycol distearate 2.0Polyethylene glycol 5.0 a heterocyclic ester or 5.0 amide as definedabove Ethanol 2.0 Perfume 0.3 Purified water 69.7 

Into 69.7 of purified water are added 5.0 g of sodium laurylsulfate, 5.0g of triethanolamine laurylsulfate, 6.0 g of betainelauryldimethylaminoacetate. Then a mixture obtained by adding 5.0 g of aheterocyclic ester or amide, 5.0 g of polyethylene glycol, and 2.0 g ofethylene glycol distearate to 2.0 g of ethanol, followed by stirring,and 0.3 g of perfume are successively added. The resulting mixture isheated and subsequently cooled to obtain a shampoo.

The shampoo may be used on the scalp once or twice per day.

Example 10

A patient is suffering from alopecia senilis. A heterocyclic ester oramide as identified above, or a pharmaceutical composition comprisingthe same, may be administered to the patient. Increased hair growth isexpected to occur following treatment.

Example 11

A patient is suffering from male. pattern alopecia. A heterocyclic esteror amide as identified above, or a pharmaceutical composition comprisingthe same, may be administered to the patient. Increased hair growth isexpected to occur following treatment.

Example 12

A patient is suffering from alopecia areata. A heterocyclic ester oramide as identified above, or a pharmaceutical composition comprisingthe same, may be administered to the patient. Increased hair growth isexpected to occur following treatment.

Example 13

A patient is suffering from hair loss caused by skin lesions. Aheterocyclic ester or amide as identified above, or a pharmaceuticalcomposition comprising the same, may be administered to the patient.Increased hair growth is expected to occur following treatment.

Example 14

A patient is suffering from hair loss caused by tumors. A heterocyclicester or amide as identified above, or a pharmaceutical compositioncomprising the same, may be administered to the patient. Increased hairgrowth is expected to occur following treatment.

Example 15

A patient is suffering from hair loss caused by a systematic disorder,such as a nutritional disorder or an internal secretion disorder. Aheterocyclic ester or amide as identified above, or a pharmaceuticalcomposition comprising the same, may be administered to the patient.Increased hair growth is expected to occur following treatment.

Example 16

A patient is suffering from hair loss caused by chemotherapy. Aheterocyclic ester or amide as identified above, or a pharmaceuticalcomposition comprising the same, may be administered to the patient.Increased hair growth is expected to occur following treatment.

Example 17

A patient is suffering from hair loss caused by radiation. Aheterocyclic ester or amide as identified above, or a pharmaceuticalcomposition comprising the same, may be administered to the patient.Increased hair growth is expected to occur following treatment.

The invention being thus described, it will be obvious that the same maybe varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the invention and all suchmodifications are intended to be included within the scope of thefollowing claims.

We claim:
 1. A method for treating alopecia or promoting hair growth inan animal in need thereof, which comprises administering to said animalan effective amount of a nitrogen-containing heterocyclic compoundhaving two or more heteroatoms, wherein said compound has a substituent—C(W)—C(Y)— which is attached to a nitrogen atom of the heterocyclicring, wherein W and Y are independently selected from the groupconsisting of O, S, CH₂, and H₂, and wherein said compound isadditionally substituted with a ester or amide substituent attached toany atom of the heterocyclic ring other than said nitrogen atom,provided that said ester or amide substituent is not an N-oxide of anester or amide and further provided that said amide substituent islinked to the heterocyclic ring with a carbon-carbon bond.
 2. The methodof claim 1, wherein the compound is non-immunosuppressive.
 3. The methodof claim 1, wherein the compound has an affinity for an FKBP-typeimmunophilin.
 4. The method of claim 3, wherein the FKBP-typeimmunophilin is FKBP-12.
 5. A method for treating alopecia or promotinghair growth in an animal, which comprises administering to said animalan effective amount of a compound of formula I

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein: A and B, together with the nitrogen and carbon atoms to whichthey are respectively attached, form a 5-7 membered saturated orunsaturated heterocyclic ring which has, in addition to the nitrogenatom, one or more additional O, S, SO, SO₂, N, NH, or NR₁ heteroatom(s);X is O or S; Z is O, NH, or NR₁; W and Y are independently O, S, CH₂, orH₂; R₁ is C₁-C₆ straight or branched chain alkyl or C₂-C₆ straight orbranched chain alkenyl, which is substituted with one or moresubstituent(s) independently selected from the group consisting of(Ar₁)_(n), C₁-C₆ straight or branched chain alkyl or C₂-C₆ straight orbranched chain alkenyl substituted with (Ar₁)_(n), C₃-C₈ cycloalkyl,C₁-C₆ straight or branched chain alkyl or C₂-C₆ straight or branchedchain alkenyl substituted with C₃-C₈ cycloalkyl, and Ar₂; n is 1 or 2;R₂ is either C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl or Ar₁,wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is eitherunsubstituted or substituted with one or more substituent(s)independently selected from the group consisting of C₁-C₄ straight orbranched chain alkyl, C₂-C₄ straight or branched chain alkenyl, andhydroxy; and Ar₁ and Ar₂ are independently an alicyclic or aromatic,mono-, bi- or tricyclic, carbo- or heterocyclic ring, wherein the ringis either unsubstituted or substituted with one or more substituent(s)independently selected from the group consisting of halo, hydroxy,nitro, trifluoromethyl, C₁-C₆ straight or branched chain alkyl, C₂-C₆straight or branched chain alkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy,phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-6members; and wherein the heterocyclic ring has 1-6 heteroatom(s)independently selected from the group consisting of O, N, and S.
 6. Themethod of claim 5, wherein the mono- or bicyclic, carbo- or heterocyclicring is selected from the group consisting of naphthyl, indolyl, furyl,thiazolyl, thienyl, pyridyl, quinolinyl, isoquinolinly, fluorenyl, andphenyl.
 7. The method of claim 5, wherein the one or more additionalheteroatom(s) in the 5-7 membered saturated or unsaturated heterocyclicring is NH or NR₁.
 8. The method of claim 5, wherein the compound is offormula II

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein: A, B and C are independently CH₂, O, S, SO, SO₂, NH, or NR₁,provided that A, B and C are not all CH₂; R₁ is C₁-C₅ straight orbranched chain alkyl or C₂-C₅ straight or branched chain alkenyl, whichis substituted with one or more substituent(s) independently selectedfrom the group consisting of (Ar₁)_(n), and C₁-C₆ straight or branchedchain alkyl or C₂-C₆ straight or branched chain alkenyl substituted with(Ar₁)_(n); n is 1 or 2; R₂ is either C₁-C₉ straight or branched chainalkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇cycloalkenyl, or Ar₁; and Ar₁ is an alicyclic or aromatic, mono-, bi- ortricyclic, carbo- or heterocyclic ring, wherein the ring is eitherunsubstituted or substituted with one or more substituent(s)independently selected from the group consisting of halo, hydroxy,nitro, trifluoromethyl, C₁-C₆ straight or branched chain alkyl, C₂-C₆straight or branched chain alkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy,phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-6members; and wherein the heterocyclic ring has 1-6 heteroatom(s)independently selected from the group consisting of O, N, and S.
 9. Themethod of claim 8, wherein: A is CH₂; B is CH₂ or S; C is CH₂ or NH; R₁is selected from the group consisting of 3-phenylpropyl and3-(3-pyridyl)propyl; and R₂ is selected from the group consisting of1,1-dimethylpropyl, cyclohexyl, and tert-butyl.
 10. The method of claim9, wherein: B is CH₂; C is NH; and R₁ is 3-phenylpropyl.
 11. The methodof claim 9, wherein: B is S; and C is CH₂.
 12. The method of claim 8,wherein the compound is selected from the group consisting of:3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-thiazolidine)carboxylate;and3-(3-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-thiazolidine)carboxylate; or a pharmaceutically acceptable salt, ester, or solvatethereof.
 13. The method of claim 5, wherein the compound is of formulaIII

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein: A, B, C and D are independently CH₂, O, S, SO, SO₂, NH, or NR₁,provided that A, B, C and D are not all CH₂; R₁ is C₁-C₅ straight orbranched chain alkyl or C₂-C₅ straight or branched chain alkenyl, whichis substituted with one or more substituent(s) independently selectedfrom the group consisting of (Ar₁)_(n) and C₁-C₆ straight or branchedchain alkyl or C₂-C₆ straight or branched chain alkenyl substituted with(Ar₁)_(n); n is 1 or 2; R₂ is either C₁-C₉ straight or branched chainalkyl, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇cycloalkenyl, or Ar₁; and Ar₁ is an alicyclic or aromatic, mono- , bi-or tricyclic, carbo- or heterocyclic ring, wherein the ring is eitherunsubstituted or substituted with one or more substituent(s)independently selected from the group consisting of halo, hydroxy,nitro, trifluoromethyl, C₁-C₆ straight or branched chain alkyl, C₂-C₆straight or branched chain alkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy,phenoxy, benzyloxy, and amino; wherein the individual ring size is 5-6members; and wherein the heterocyclic ring has 1-6 heteroatom(s)independently selected from the group consisting of O, N, and S.
 14. Themethod of claim 13, wherein: A is CH₂; B is CH₂; C is S, O or NH; D isCH₂; R₁ is selected from the group consisting of 3-phenylpropyl and(3,4,5-trimethoxy)phenylpropyl; and R₂ is selected from the groupconsisting of 1,1-dimethylpropyl, cyclohexyl, tert-butyl, phenyl, and3,4,5-trimethoxyphenyl.
 15. The compound of claim 14, wherein: C is NH;and R₂ is 1,1-dimethylpropyl or phenyl.
 16. A method for treatingalopecia or promoting hair growth in an animal in need thereof, whichcomprises administering to said animal an effective amount of a compoundof formula IV

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein: V is C, N, or S; A and B, taken together with V and the carbonatom to which they are respectively attached, form a 5-7 memberedsaturated or unsaturated heterocyclic ring which has, in addition to V,one or more heteroatom(s) independently selected from the groupconsisting of O, S, SO, SO₂, N, NH, and NR; R is either C₁-C₉ straightor branched chain alkyl, C₂-C₉ straight or branched chain alkenyl,C₃-C_(g) cycloalkyl, C₅-C₇ cycloalkenyl, or Ar₃, wherein R is eitherunsubstituted or substituted with one or more substituent(s)independently selected from the group consisting of halo, haloalkyl,carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C₁-C₆ straight orbranched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₁-C₄alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, thioalkyl, alkylthio,sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, and Ar₄; Ar₃and Ar₄ are independently an alicyclic or aromatic, mono- , bi- ortricyclic, carbo- or heterocyclic ring; wherein the individual ring sizeis 5-8 members; wherein said heterocyclic ring has 1-6 heteroatom(s)independently selected from the group consisting of O, N, and S; X is Oor S; Z is O, NH, or NR₁; W and Y are independently O, S, CH₂, or H₂; R₁is C₁-C₆ straight or branched chain alkyl or C₂-C₆ straight or branchedchain alkenyl, which is substituted with one or more substituent(s)independently selected from the group consisting of (Ar₁)_(n), C₁-C₆straight or branched chain alkyl or C₂-C₆ straight or branched chainalkenyl substituted with (Ar₁)_(n), C₃-C₈ cycloalkyl, C₁-C₆ straight orbranched chain alkyl or C₂-C₆ straight or branched chain alkenylsubstituted with C₃-C₈ cycloalkyl, and Ar₂; n is 1 or 2; and R₂ iseither C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl or Ar₁,wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is eitherunsubstituted or substituted with one or more substituent(s)independently selected from the group consisting of C₁-C₄ straight orbranched chain alkyl, C₂-C₄ straight or branched chain alkenyl, andhydroxy.